Kamran Safdar

Treatment of established recurrent hepatitis C in liver-transplant recipients with pegylated interferon-alfa-2b and ribavirin therapy

Introduction. The management issues of transplant patients with hepatitis C virus (HCV) are complex, and interferon therapy is often ineffective. We present data from a retrospective review in liver-transplant recipients suffering from HCV recurrence that were treated with pegylated alpha-2b interferon and ribavirin. Methods. A retrospective review of transplant recipients that received combination pegylated alpha-2b interferon (1.5 mcg/kg/wk) and ribavirin (400–600 mg/day) therapy intended for at least 48 weeks. Complications were recorded and included neutropenia (<750 cells), anemia (hemoglobin <8 g) with and without treatment consisting of blood transfusions, erythropoietin, or dose reduction of ribavirin, and depression. The diagnosis of HCV recurrence was determined by an increase in liver chemistries, histopathologic findings with inflammation along with viral recurrence using the COBAS AMPLICOR HCV test. Results. Fifty-seven liver-transplant recipients were included, 29 naïve (group 1) to therapy and 28 nonresponders (group 2) to at least 6 months of interferon and ribavirin therapy. Eight (27.6%) patients in group 1 and six (21%) patients in group 2 were HCV nondetectable at the end of 48 weeks of therapy. Ribavirin therapy was decreased in 13 of 29 (45%) for group 1 and 11 of 28 (39%) in group 2. Therapeutic interventions were 4 of 57 (7%) blood transfusions, 23 of 57 (40%) erythropoietin, and 17 of 57 (30%) filgrastim. Conclusion. Combination pegylated interferon with ribavirin appears to effective therapy in HCV recurrence and in HCV nonresponsive to interferon and ribavirin. This data reveals the difficulty and caution that must be taken when treating HCV-R liver-transplant recipients with combination pegylated alpha-2b interferon and ribavirin therapy.

A retrospective review of liver transplant patients treated with sirolimus from a single center: an analysis of sirolimus-related complications.

Background. Sirolimus (SRL) is a powerful immunosuppressant used primarily in calcineurin inhibitors (CNI)-related nephrotoxicity. However, reports of drug-related side effects are increasing. The aim of our report is to review the frequency and timing of these complications within our transplant patient population. Methods. We retrospectively reviewed the medical records of liver-transplanted patients treated with sirolimus between November 1998 and April 2002. The data collected included SRL serum levels, frequency of reported and documented SRL-related side effects, and survival outcomes. Statistical evaluation included Pearson chi-square and the Fisher’s exact tests. Results. Overall, 205 patients were identified, with 30 patients removed from the analysis for different reasons. Of the remaining 175 patients, 91 (52%) patients developed a complication other than an increase in serum triglycerides and/or cholesterol. The most frequent complications were: bilateral lower extremity edema (57.1%), dermatitis (25.3%), oral ulcers (24.2%), joint pain (23.0%), pleural effusion (16.5%) and increase in abdominal girth (9.9%). Other complications included: generalized edema (5.5%), pericardial effusion (5.5%), facial edema (2.2%), and upper extremity edema (1.3%). In addition, we reported two cases of hepatic artery thrombosis, one case of wound dehiscence with evisceration that required surgical repair, and one case of skin cancer. Interestingly, we found that a previous history of myocardial ischemia correlates with the development of SRL side effects. Conclusions. SRL is a powerful immunosuppressant but not devoid of side effects. These results have elevated our level of suspicion when instituting SRL and may help with early recognition and prevention of drug related complications.

Outcomes in liver transplant recipients with hepatitis B virus: Resistance and recurrence patterns from a large transplant center over the last decade

Hepatitis B virus (HBV) recurrence following liver transplantation (LTx) has been controllable primarily with the use of hepatitis B immune globulin (HBIg) and lamivudine (LAM). However, HBV resistance to LAM and/or HBIg has become an increasing problem prompting the use of newer antiviral agents. The purpose of our study was to investigate the association between therapy, HBV breakthrough, and allograft / patient survival in HBV‐positive liver transplant recipients. We performed a retrospective review of the medical records of patients that were transplanted for HBV from June 1994 to May 2003. A total of 92 patients, positive for either hepatitis B surface antigen (HBsAg) or HBV deoxyribonucleic acid (DNA) pretransplant, received LAM monotherapy or HBIg (6 months) plus LAM therapy post–liver transplant. HBV breakthrough post‐LTx was noted in 14 patients. All patients had detectable HBV DNA prior to liver transplantation; none of the patients that were HBV DNA negative prior to transplant had detectable HBV DNA posttransplant. Of these 14, 9 patients (64%) were switched from LAM to adefovir dipivoxil (ADF) and 5 patients (36%) to tenofovir disoproxil fumarate (TNV). In conclusion, pre‐LTx HBV viremia should be considered in planning post‐LTx prophylaxis. Trials to evaluate oral antiviral agents in combination with or without HBIg therapy are needed. (Liver Transpl 2004;10:1372–1378.)

Factors that identify survival after liver retransplantation for allograft failure caused by recurrent hepatitis C infection

Hepatitis C virus (HCV) is becoming the most common indication for liver retransplantation (ReLTx). This study was a retrospective review of the medical records of liver transplant patients at our institution to determine factors that would identify the best candidates for ReLTx resulting from allograft failure because of HCV recurrence. The patients were divided into 2 groups on the basis of indication for initial liver transplant. Group 1 included ReLTx patients whose initial indication for LTx was HCV. Group 2 included patients who received ReLTx who did not have a history of HCV. We defined chronic allograft dysfunction (AD) as patients with persistent jaundice (> 30 days) beginning 6 months after primary liver transplant in the absence of other reasons. HCV was the primary indication for initial orthotopic liver transplantation (OLT) in 491/1114 patients (44%) from July 1996 to February 2004. The number of patients with AD undergoing ReLTx in Groups 1 and 2 was 22 and 12, respectively. The overall patient and allograft survival at 1 year was 50% and 75% in Groups 1 and 2, respectively (P = .04). The rates of primary nonfunction and technical problems after ReLTx were not different between the groups. However, the incidence of recurrent AD was higher in Group 1 at 32% versus 17% in Group 2 (P = .04). Important factors that predicted a successful ReLTx included physical condition at the time of ReLTx (P = .002) and Child‐Turcotte‐Pugh score (P = .008). In conclusion, HCV is associated with an increased incidence of chronic graft destruction with a negative effect on long‐term results after ReLTx. The optimum candidate for ReLTx is a patient who can maintain normal physical activity. As the allograft shortage continues, the optimal use of cadaveric livers continues to be of primary importance. The use of deceased donor livers in patients with allograft failure caused by HCV remains a highly controversial issue. (Liver Transpl 2004;10:1497–1503.)

Prediction of sustained virological response in liver transplant recipients with recurrent hepatitis C virus following combination pegylated interferon alfa‐2b and ribavirin therapy using tissue hepatitis C virus reverse transcriptase polymerase chain reaction testing

The optimal duration of therapy for pegylated interferon combined with ribavirin in recurrent Hepatitis C virus (HCV) following liver transplantation is not known. We wanted to determine if testing for HCV in liver tissue by reverse transcriptase polymerase chain reaction (RT‐PCR) was superior in predicting sustained virological response (SVR) in comparison to standard HCV ribonucleic acid (RNA) detection in the serum. All recipients received combination pegylated alpha‐2b interferon (1.5 mcg / kg) and ribavirin (200–600mg / d) therapy for at least 48 weeks of therapy and were found to have nondetectable HCV RNA by PCR serum testing at the end of therapy. Sustained virological response (SVR) was defined as nondetectable serum HCV RNA at 6 months post treatment withdrawal. Ten liver transplant recipients were included in the study; mean time from transplantation was 29.2 months. All had nondetectable serum HCV RNA by RT‐PCR. In hepatic tissue 7/10 patients HCV RNA was found to be positive by RT‐PCR while 3/10 had nondetectable HCV RNA in their liver by RT‐PCR. SVR was attained in all 3/10 that were hepatic tissue HCV PCR negative after 12 months of combination therapy. In conclusion, direct detection of HCV RNA by RT‐PCR of liver tissue appears to more effectively predict SVR following pegylated interferon and ribavirin therapy than the conventional use of serum. (Liver Transpl 2004;10:595–598.)

Impact of geographic location on access to liver transplantation among ethnic minorities.

Background. Recent reports have documented ethnic disparity in access to health care. This disparity appears to exist in organ transplantation and the contributing factors include lack of insurance as well as poor socioeconomic status. The role of geographic location and ethnic composition on accessibility to liver transplantation (LT) is unclear. Therefore, the aim of this study was to determine ethnic transplantation trends based on United Network for Organ Sharing (UNOS) regions. Methods. Using the UNOS database, we identified all adults (≥18 years) that received LT between 2000 and 2005. We excluded multiorgan transplants and living donor transplantation. The data collected included ethnicity, transplantation rate, and UNOS region. Data were analyzed using the &khgr;2 test. Results. A total of 30,311 patients received a LT during the study period. Of these, 22,673 (74.8%) were white, 3621 (12%) were Hispanic, 2490 (8.2%) were African Americans, and the rest of other ethnic groups (5%). Liver transplantation based on ethnicity was region specific, with the lowest for African Americans in region 6 (2.7%), for Hispanics in region 11 (2.2%), and for whites in region 5 (57.6%), respectively. There was no consistent correlation between the ethnicity of the recipients and the ethnic composition of the geographic location (region). Conclusion. Significant variations in access to liver transplantation for ethnic minorities exist across geographic lines. Understanding the interaction between ethnic minorities with end-stage liver disease in a geographic location and a transplant center will be invaluable as a first step in identifying the key nonmedical factors that play a role in this disparity.

Liver Transplantation Trends for Older Recipients : Regional and Ethnic Variations

Background. Liver transplantation (LT) provides long-term survival for adults with end-stage liver disease. As a result of improved survival and an aging United States population the demand for LT in older patients is expected to increase. The aim of this study was to describe the transplantation trends in the older recipient (older than 65 years). Methods. Using the United Network for Organ Sharing database, we identified LT recipients between 1990 and 2006. We used Kaplan-Meier method to calculate overall survival (1, 3, 5 and 10 years) and Cox regression for predictors of survival. Results. During the study period 5630 (7.6%) LT recipients were older than 65 years. There were 4256 (79.4%) whites, Hispanic (10.3%), African Americans (AA) (3.6%), and rest (6.7%). There was an increase in LT for older than 65 years from 4.1% in 1990 to 10.2% in 2006 (P=0.002) and a regional variation (P<0.001). The 10-year patient and graft survival was 60% and 57% for less than 65 years versus 42% and 40% for more than 65 years (P<0.0001). With age stratification (65–75 years vs. >75 years), there was no difference in survival but when adjusted for race there was a significant difference in graft survival with a 10 year (white 40%, Hispanic 44%, and AA 19%) (P=0.04). Conclusion. The demand for LT in recipients older than 65 years is increasing. Although their survival is lower in comparison with recipients less than 65 years, there seems to be no difference in unadjusted survival with age stratification above 65 years. Among ethnic minorities, there was a disproportionately lower percentage of African Americans LT and a decreased survival.

Consumption of dietary supplements in a liver transplant population

The extensive use of alternative medicine products, herbal remedies, and vitamins in large doses has reached an all time high in the general public. Some agents are reported and advertised as immune stimulants and may interfere with patients suffering from immune modification, autoimmune diseases, or transplant recipients. In this report, we will present an investigation into the use of herbal remedies and vitamins in our liver transplant population. We performed an investigation using a questionnaire to determine the use of herbal products and vitamins in our liver transplant population. Medical records were reviewed for each liver transplant recipient that admitted to consuming herbal products or vitamins. Information collected included patient demographics, transplant related information, laboratory tests, outcomes, and herbs or vitamin products used. A total of 290 patients completed and returned the questionnaire. We found 156 admitting to taking more than a standard multivitamin and/or an herbal remedy. All patients were treated with steroids for allograft rejection and experienced a recurrence of amino transaminases following the removal of steroids. Further investigation into dietary supplements using a patient questionnaire form revealed that nearly 50% of patients admitted to using vitamins following transplantation, while 19% used herbal remedies combined with vitamins, most admitting to silymarin. One recipient was ingesting colostrum and required admission for the management of allograft rejection, while 5 patients had consumed large amounts of echinacea or CoEnzyme Q‐10 and experienced elevations in their transaminases that resolved with discontinuation of the herb. The review also identified 4 patients with primary biliary cirrhosis and with transaminase elevation (mean values of aspartate aminotransferase and alanine aminotransferase levels of 88 and 95, respectively). All recipients were consuming vitamins, in particular high doses of vitamin E (tocopherol), more than 1 gram per day. All of the transplant recipients were instructed to discontinue all vitamin E products and the amino transaminases resolved over the following 30 to 60 days. In conclusion, this information reveals that a significant proportion of our liver transplant recipients consume herbal remedies. The results of this report suggest that transplant teams need to question each recipient about the use of herbal and vitamin remedies and educate them regarding the potential hazards. (Liver Transpl 2004;10:881–885.)

Adult onset urea cycle disorder in a patient with presumed hepatic encephalopathy.

Deficiency of any of the 5 enzymes in the urea cycle results in the accumulation of ammonia, leading to encephalopathy; which if untreated, can be lethal and produce devastating neurologic sequelae in long-term survivors. We hereby present an interesting case that presented with hyperammonemia and encephalopathy; later found to have an urea cycle defect.

Hepatitis C transmission from seropositive, nonviremic donors to non–hepatitis C liver transplant recipients

Breakthroughs in hepatitis C virus (HCV) treatment and rising rates of intravenous drug use have led to an increase in the number of organ donors who are HCV antibody–positive but serum nucleic acid test (NAT)–negative. The risk of HCV transmission from the liver grafts of these donors to recipients is unknown. To estimate the incidence of HCV transmission, we prospectively followed 26 consecutive HCV antibody–negative (n = 25) or NAT‐negative (n = 1) transplant recipients who received a liver graft from donors who were HCV antibody–positive but serum NAT‐negative between March 2016 and March 2017. HCV transmission was considered to have occurred if recipients exhibited a positive HCV PCR test by 3 months following transplantation. Drug overdose was listed as the cause of death in 15 (60%) of the donors. One recipient died 18 days after transplantation from primary graft nonfunction and was excluded. Of the remaining 25 recipients, HCV transmission occurred in 4 (16%), at a median follow‐up of 11 months, all from donors who died of drug overdose. Three of these patients were treated with direct‐acting antiviral therapy, with two achieving a sustained virologic response and one an end‐of‐treatment response. One patient with HCV transmission died after a complicated postoperative course and did not receive antiviral therapy. Conclusion: In this prospective cohort of non‐HCV liver recipients receiving grafts from HCV antibody–positive/NAT‐negative donors, the incidence of HCV transmission was 16%, with the highest risk conferred by donors who died of drug overdose; given the availability of safe and highly effective antiviral therapies, use of such organs could be considered to expand the donor pool. (Hepatology 2018;67:1673‐1682).